Project Summary This application is an Emergency Competitive Revision (PA-20-135) to existing NIH award K24AI150991 proposing immediate work to help address the urgent need for research on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19). While the majority of cases of COVID19 result in mild symptoms, some progress to respiratory and multi-organ failure. The case fatality rate for COVID19 varies widely according to age group and underlying medical comorbidities. There an urgent need to improve our understanding of mechanisms that underlie the heterogeneity of disease severity with SARS-CoV2 infection between individuals and explain why children are more resistant to developing severe COVID-19 than adults. Such knowledge will be critical in developing novel therapeutic interventions to treat and prevent SARS-CoV2 infection and COVID19 disease. One theory for the widely varying COVID-19 disease severity between children and adults, and even between older adults, is heterogeneity between individuals in how the virus gains entry to airway epithelial cells (AECs). The spike protein of SARS CoV2 uses angiotensin converting enzyme 2 (ACE-2) as its cell binding site and the membrane serine protease TMPRSS2 primes the spike protein. In humans it is unknown if epithelial expression of ACE-2 or TMPRSS2 are lower among children as compared to adults. In animals two common antihypertension medications (angiotensin II receptor blockers, ARBs; and angiotensin-converting-enzyme inhibitors, AECi) increase ACE-2 expression, fueling debate about the effect of these drugs on the infectivity of SARS-CoV2 and risk of COVID-19. We recently observed that ACE-2 expression by bronchial AECs from children increases following infection with human rhinovirus, prompting us to question whether a recent rhinovirus infection modulates SARS-CoV2 infection and the risk of COVID-19. The first aim of this Competitive Revision is to determine whether bronchial AEC expression of ACE-2 varies with age or pre-infection with human rhinovirus, and whether treatment of AECs with ARBs, ACEi or exogenous ACE-2, modulate SARS CoV2 infectivity and replication. A second potential explanation for varying COVID-19 disease severity is heterogeneity in type I and III interferon (IFN I/III) responses between individuals to SARS-CoV2. The second aim of this Competitive Revision, which logically extends from the goals of the applicant?s parent award (K24AI150991), is to determine if heterogeneity of AEC IFN I/III responses following SARS-CoV2 infection of primary AECs from children and adults is associated with viral replication, and whether the drug azithromycin increases AEC IFN I/III responses to SARS-CoV2 and reduces viral replication. Finally, this supplement to K24AI150991 will also support the direct mentorship of 3 junior faculty physician-scientists and a PhD candidate who are all engaged in mechanistic COVID-19 patient-oriented research under the applicant?s mentorship or co-mentorship.